ArticleThe Journal of physiology2007
Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor.
Article in The Journal of physiology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- Pharmacological Strategy for Congenital Myasthenic Syndrome with CHRNE Mutations: A Meta-Analysis of Case Reports.Current neuropharmacology · 2021Pooled it
- Reduction of the CaFrontiers in cellular neuroscience · 2025Review
- Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.International journal of molecular sciences · 2023Review
- The Distribution of Charged Amino Acid Residues and the CaFrontiers in molecular neuroscience · 2017Article
- Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating.Human mutation · 2016Article
- Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor.Molecular biology and evolution · 2014Article
- Riluzole blocks human muscle acetylcholine receptors.The Journal of physiology · 2012Article
- Mutant human β4 subunit identified in amyotrophic lateral sclerosis patients impairs nicotinic receptor function.Pflugers Archiv : European journal of physiology · 2011Article
- What have we learned from the congenital myasthenic syndromes.Journal of molecular neuroscience : MN · 2010Review
- Decremental response to high-frequency trains of acetylcholine pulses but unaltered fractional Ca2+ currents in a panel of "slow-channel syndrome" nicotinic receptor mutants.The Journal of general physiology · 2009Article
- Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients.Annals of neurology · 2008Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
The epsilon subunit of the human endplate ACh receptor (AChR) is a key determinant of the large fraction of the ACh-evoked current carried by Ca2+ ions (P(f)). Consequently, missense mutations in the epsilon subunit are potential targets for altering the P(f) of human AChR. In this paper we investigate the effects of two pathogenic point mutations in the M2 transmembrane segment AChR epsilon subunit, epsilonT264P and epsilonV259F, that cause slow-channel syndromes (SCS). When expressed in GH4C1 cells, the mutant receptors subunits raise Ca2+ permeability of the receptors approximately 1.5 and approximately 2-fold above that of wild-type, to attain P(f) values of 11.8% (epsilonT264P) and 15.4% (epsilonV259F). The latter value exceeds most P(f) values reported to date for ligand-gated ion channels. Consistent with these findings, the biionic Ca2+ permeability ratio (P(Ca)/P(Cs)) of the mutant AChRs is also increased. Upon repetitive stimulation with ACh, the mutant receptors show an enhanced current run-down compared with wild-type, leading to a strong reduction of their function. We propose that the enhanced Ca2+ permeability of the mutant receptors overrides the protective effect of desensitization and, together with the prolonged opening events of the AChR channel, is an important determinant of the excitotoxic endplate damage in the SCS.
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